Process for the asymmetric hydrogenation of carbonyl compounds obtained

ABSTRACT

The asymmetric hydrogenation of carbonyl compounds is carried out in the presence of at least one transition metal complex MZq(M=metal of group VIII of the Periodic Classication; Z=ligand selected among the atoms and the molecules which may complex the metal M; and q=degree of corrdination of M) and of at least one chiral phosphorous-containing ligand having formula (I), wherein R is hydrocarbonated radical (alkyl, cycloalkyl and aryl); R 1  is H, hydrocarbonated radical or PR 2  ; R 2  is H or hydrocarbonated radical R 3 ,R 4 , necessarily different, are H and optionally functionalized hydrocarbonated radicals; R 5  and R 6  are H and optionally functionalized hydrocarbonated radicals; one of the radicals R 3  and R 4  possibly carrying a function - OPR 2  or NPR 2 , R 5  and R 6  being in this case H when R 1  is PR 2  ; R 2  and R 3  and the atoms of N and C which cary them respectively forming a heterocycle; or R 2  and R 5 , the atoms of N and C which carry them respectively and the intermediate C atom possibly forming a heterocycle. ##STR1##

This application is a continuation of application Ser. No. 07/165,111filed Apr. 1, 1988, now abandoned.

The present invention relates to the enantioselective synthesis oforganic compounds and it relates more particularly to the asymmetrichydrogenation of carbonyl groups, catalyzed by transition metalcomplexes containing chiral phosphorus-containing ligands.

Although a reduction catalysed in a homogeneous phase by Wilkinson typecomplexes, Rh[PPh₃ ]₃ Cl, prove to be very effective with respect to theasymmetric synthesis of α-amino acids from olefinic precursors (H. B.Kagan, "Asymmetric synthesis using organometallic catalysts,Comprehensive organometallic chemistry, G. Wilkinson Ed. (1982) Vol. 8,463, Pergamon Press, London), it is inoperative, however, in thesynthesis of chiral alcohols from ketones.

Moreover, in asymmetric catalysis, it is well known that the differenttypes of ligands are specific for a given starting compound (substrate).

It has now been discovered that asymmetric hydrogenation of carbonylcompounds could be envisaged with excellent results by the use ofligands obtained in a single stage starting with chiral α-amino alcoholswhich are commercially produced or which are derived from naturalα-amino acids, such ligands having already been described in EuropeanPatent Application EP-A-136,210 for other syntheses (such as asymmetrichydrogenation of dehydroamino acids) and by M. Petit, A. Mortreux, F.Petit, G. Buono and G. Peiffer in "Nouv. J. chim. 10 (7) (1983) 593".

Moreover, it has surprisingly been discovered that the choice of areaction medium in which the substrate is soluble whereas the finalproduct is insoluble enables, on the one hand, high optical yields to beachieved and, on the other hand, very high substrate:metal catalystmolar ratios (which may range up to 5000) to be employed, which hasnever been possible to achieve until now. Thus, these ratios are 50 and200 in the case of the asymmetric hydrogenations of the carbonyl group,described by K. Yamamoto et al. and by K. Tani et al. respectively, thevalue 200 representing the upper limit which could be achieved so far.

The subject of the present invention is a process for the asymmetrichydrogenation of carbonyl compounds, which is carried out in thepresence, on the one hand, of at least one transition metal complex offormula:

    MZq

in which

M is a group VIII metal of the Periodic Table;

Z represents one or more among the atoms and molecules capable ofcomplexing the metal M; and

q is the coordination number of the metal M,

and, on the other hand, of at least one chiral phosphoruscontainingligand, wherein a compound represented by formula (I) is chosen as thechiral phosphorus-containing ligand: ##STR2## in which formula: Rrepresents a hydrocarbon radical chosen from amongst straight-chain orbranched alkyl, cycloalkyl or aryl radicals;

R¹ represents a hydrogen, a hydrocarbon radical or a --PR₂ residue;

R² represents a hydrogen or a hydrocarbon radical;

R³ and R⁴, which are necessarily different, are chosen from amongsthydrogen atoms and hydrocarbon radicals optionally carrying at least onegroup chosen from amongst alcohol, thiol, thioether, amine, imine, acid,ester, amide and ether groups; and

R⁵ and R⁶ are chosen from amongst hydrogen atoms and optionallyfunctionalized hydrocarbon radicals;

it being possible for one of the radicals R³ and R⁴ to carry an --OPR₂or --NPR₂ group, both R⁵ and R⁶ being, in this case, equal to hydrogenwhen R¹ represents --PR₂,

it being possible for R² and R³ and the nitrogen and carbon atoms whichcarry them respectively to together form a heterocycle;

or alternatively, it being possible for R² and R⁵, the nitrogen andcarbon atoms which carry them respectively and the intermediate carbonatoms to together form a heterocycle.

This family of ligands may be divided into three sub-families dependingon the number of dihydrocarbylphosphine (--PR₂) radicals present, i.e.monodentate chelates (in which R¹ does not refer to --PR₂ and R³ doesnot carry the residue --OPR₂ or --NPR₂); bidentate chelates (in whicheither R¹ represents --PR₂ in which case R³ and R⁴ do not carry a --OPR₂or --NPR₂ group, or R³ or R⁴ carry an --OPR₂ or --NPR₂ residue in whichcase R¹ cannot represent --PR₂) and tridentate chelates (in which R¹represents a --PR₂ residue and R³ carries an --OPR₂ or --NPR₂ residue).

As alkyl radicals for R, there will be mentioned C₁ -C₁₂, especially C₁-C₆, alkyl radicals, for example methyl, ethyl, isopropyl and tert-butylradicals. As cycloalkyl radicals for R, there will be mentionedcyclopentyl and cyclohexyl radicals. As aryl radicals for R, there willbe mentioned the phenyl radical. Alkyl and cycloalkyl radicals arepreferred for R.

As hydrocarbon radical for R¹ or R², there could be mentioned alkylradicals, especially C₁ -C₁₂ alkyl radicals, for example the methylradical.

Examples of hydrocarbon radicals for R³ or R⁴ are, in particular,methyl, isopropyl, neobutyl, isobutyl, isoamyl, hydroxymethyl,n-hydroxyethyl, iso-hydroxyethyl, n-aminobutyl, 4-methyleneimidazolyl,N-n-propylguanidyl, ethanoyl, acetamido, n-propionyl, n-propionamido,phenyl, benzyl, para-hydroxybenzyl, 3-methyleneindolyl, mercaptomethyl,methylthioethyl and NH₂ --C(═NH)--NH--(CH₂)₃ -- radicals.

As hydrocarbon radicals for R⁵ or R⁶, there will be mentioned, inparticular, C₁ -C₁₂ alkyl radicals.

When the ligands of formula (I) contain a heterocycle, formed with theradicals R² and R³ or R² and R⁵, this heterocycle is especially a 5- or6-membered heterocycle.

The process for the production of these ligands of formula (I) isdescribed in European Patent Application EP-A-136,210. With regard tothe complex MZq, as metals M which can be commonly employed, there maybe mentioned iron, nickel, cobalt, rhodium, ruthenium, iridium,palladium and platinum; as atoms or molecules Z which can be commonlyemployed, there may be mentioned carbon monoxide, halogens, ethylene,norbornadiene, cyclooctadiene and acetylacetone. The coordination numberq may commonly be between 2 and 6 inclusive depending on the metal Mand/or the ligand Z employed.

Where appropriate, the hydrogenation reaction according to the inventionmay be carried out in the presence of at least one agent capable oftaking up a ligand Z from the constituent MZq, it being possible forthis agent to be either an acid containing an anion A⁻ which has a lowcomplexing capacity and which is sterically hindered or a metal salt ofsuch an acid, or a quantity of electricity applied by electrolysis at anapplied cathode potential. Anion A⁻ which has a low complexing capacityand which is sterically hindered especially means the anionsperchlorate, tetrafluoroborate, tetraphenylborate andhexafluorophosphate. The metal salts which can be employed are mainlythose of silver and thallium.

This enantioselective synthesis reaction may be carried out in thepresence of at least one activator chosen from amongstaluminum-containing derivatives of formula AlR'_(n) X_(3-n) in which nhas a value from 0 to 3, X is a halogen atom and R' an alkyl radicalcontaining from 1 to 12 carbon atoms.

The complex MZq and the ligand of formula (I) are generally in a molarratio ligand:complex of between 1 and 10. The complex MZq and thealuminum-containing derivative mentioned above are in a molar ratioaluminum-containing derivative:complex of between 0.1 and 10. Thecomplex MZq and the agent capable of taking up at least one ligand Z aregenerally in a molar ratio agent: complex less than or equal to q, whenthis agent is an acid or a salt.

The hydrogenation reaction is generally carried out at a temperature ofbetween -20° C. and 200° C. for a period of between approximately 5minutes and 24 hours and at a pressure of between 1 and 200 bars.

Moreover, the molar ratio of the substrate (starting compound) to thecatalyst metal M may reach high values of 5000, even 10,000 or above. Inorder to be able to work at these high values, the following specificembodiment is employed:

The hydrogenation is carried out in a (solvent or solvent mixture)medium in which the substrate is substantially soluble, but in which thereaction product is insoluble or substantially insoluble and thereforeprecipitates as it is being formed.

In order to obtain a better enantiomeric excess, there may be mentioned,as solvents, aromatic hydrocarbon solvents such as benzene, toluene andxylene, aliphatic alcohols such as ethanol and aliphatic or alicyclicethers, especially ethyl ether, dioxane and tetrahydrofuran, andcompatible mixtures of these solvents.

Among starting carbonyl compounds employed in this hydrogenationreaction, there may be mentioned α-keto amides such asN-benzylbenzoylformamide (PhCOCONHCN₂ Ph) orN-benzyl-4-hydroxybenzoylformamide, which are readily synthesized by thedicarbonylation of aryl halides catalyzed by palladium complexes:α-dicarbonyl compounds such as 2-oxo-3,3-dimethyl-1,4-butanolide(pentoyllactone) and α-keto esters.

In order to make the subject of the present invention better understood,several examples of implementation thereof will now be described.

In Table I below, the nomenclature of the ligands employed is given.

                                      TABLE 1                                     __________________________________________________________________________    Nomenclature of ligands employed                                              __________________________________________________________________________     ##STR3##       CyAlaNOP  (S)-1-0-dicyclohexylphos- phino)-2-N-methyl-N-                               icyclohexylphosphinopropane                           ##STR4##       CyThreoNOP                                                                             (2R,3R)-1,3-bis-O-dicyclo-  hexylphosphino-2-N-me                             thyl-   N-dicyclohexylphosphino- butane               ##STR5##       i-PrProNOP                                                                             (S)-N-diisopropylphosphino-2- diisopropylphosphin                             oxymethyl- pyrrolidine                                ##STR6##       CyProNOP (S)-N-dicyclohexylphos- phino-2-dicyclohexylphos-                              phinoxymethyl-pyrrolidine                            ##STR7##       CyProNHOP                                                                              (S)-2-dicyclohexylphos- phinoxymethyl-pyrrolidine                             7                                                     ##STR8##       ProNOP   (S)-N-diphenylphosphino- 2-diphenylphosphinoxy-                               methyl-pyrrolidine                                    ##STR9##       Pro-BuNOP                                                                              (2S,4R)-N-diphenylphos- phino-4-diphenylphosphino                             - 2-n-butyl-formamide                                __________________________________________________________________________

I--PREPARATION OF THE LIGANDS a) Preparation of the Ligand CyProNOP

2.53 g (0.025 mol) of prolinol and 14 cm³ (0.1 mol) of NEt₃ dissolved in50 cm³ of anhydrous benzene, are introduced into a 250 cm³round-bottomed flask. 11.64 g of PCy₂ Cl dissolved in 50 cm³ of the samesolvent are added dropwise at 0° C. The reaction mixture is thenmaintained stirred for 12 hours. The solution is then filtered in orderto remove the triethylamine hydrochloride therefrom and the solventremoved under vacuum. The ligand is purified by chromatography on silicagel (eluent: ethyl acetate:NEt₂ H in a ratio of 98:2 by volume).

b) The other ligands are prepared according to the same procedure.

II--CATALYTIC HYDROGENATION OF VARIOUS CARBONYL COMPOUNDS ACCORDING TOTHE PRESENT INVENTION a) General Procedure

6.6×10⁻⁵ mmol of ligand is dissolved in 15 cm³ of anhydrous benzene in atube under nitrogen.

14.8 mg (3×10⁻⁵ mol) of the complex [Rh(cyclooctadiene)Cl]₂ are weighedinto another tube and the ligand solution is added thereto by a transfertube. The whole mixture is maintained stirred for 15 minutes.

1.2×10⁻² mole of the starting compound dissolved in 15 cm³ of benzene isintroduced, under a hydrogen atmosphere, into a thermostated (25° C.)glass reactor after purging it several times (hydrogen-vacuum). Thecatalytic solution is then transferred into the reactor and the progressof the reaction is monitored by noting the volume of hydrogen consumed.

The final product is then isolated from the reaction medium.

b) Preparation of the Final Product

1--Preparation of (S)-N-benzylmandelamide starting withN-benzylbenzoylformamide

When the reaction is complete, the solution in benzene is filtered andthe precipitate formed by the reaction is washed with 2×10 cm³ of coldbenzene. The yield is of the order of 95-100%.

The specific rotation α_(D) ²⁵ is determined on a solution intrichloromethane at a concentration of 1.09 g/100 cm³. The enantiomericexcess is calculated from the α_(D) ²⁵ for the pure product, which is+79.9° C. (see Table II).

2--Preparation of 2-hydroxy-3,3-dimethyl-1,4-butanolide starting with2-oxo-3,3-dimethyl-1,4-butanolide (pentoyllactone)

When the reaction is complete, the solvent is evaporated off and theresidue distilled under vacuum. The yield is of the order of 90-100%.

The specific rotation α_(D) ²⁵ is determined on an aqueous solution at aconcentration of 2.05 g/100 cm³. The enantiomeric excess is calculatedfrom the α_(D) ²⁵ for the pure product, which is -50.7°.

A number of examples of asymmetric hydrogenation according to theinvention, performed according to the general procedure described inparagraph IIa), are summarized in Tables II to IV below, Table IVillustrating the importance of the choice of solvent (the product ofreduction of the substrate n-benzylbenzoylformamide is soluble inethanol and not in benzene).

                                      TABLE II                                    __________________________________________________________________________    Asymmetric hydrogenation of carbonyl compounds in the                         presence of [RH-L]entities (L =ligand).                                       Starting                                                                      compound or                        Enantio-                                   substrate  Ligand         Reaction                                                                           Yield                                                                             meric Configura-                           (S)        (L)    Solvent period                                                                             (%) excess (%)                                                                          tion                                 __________________________________________________________________________    PhCOCNHCH.sub.2 Ph                                                                       CyProNOP                                                                             Benzene 6 hours                                                                            95  85.6  S                                    "          "      "       "    90    85.5.sup.(a)                                                                      S                                    "          "      "       "    98  .sup. 83.sup.(b)                                                                    S                                    "          "      "       "    98  .sup. 86.sup.(c)                                                                    S                                    "          i-PrProNOP                                                                           "       "    97  77    S                                    PhCONHCH.sub.2 Ph                                                                        CyProNOP                                                                             Benzene:                                                                              "    100 66    a.sub.D.sup.20 = +34.5                                 ethanol                (C = 1, ethanol)                                       (2:1)                                                        ##STR10## CyProNOP                                                                             Benzene 5 hours                                                                            90  49.2  R                                    "          "      "       6 hours                                                                            100 49.2  R                                    "          i-PrProNOP                                                                           "       5 hours                                                                            100 49.5  R                                    "          CyProNOP                                                                             Tetrahydro-                                                                           5 hours                                                                            100 46    R                                                      furan                                                       __________________________________________________________________________

General Experimental Conditions

[S]:[Rh]=200; [S]=0.4M; [Rh]=2×10⁻³ M

[L]=2.2×10⁻³ M

Quantity of solvent=30 cm³

Temperature=25° C.

H₂ pressure=1 bar

Specific Experimental Conditions

(a): [S]:[RH]=400; [RH]=10⁻³ M

(b): [S]:[Rh]=1000; [Rh]=4×10⁻⁴ M

(c): [S]:[Rh]=5000; [Rh]=8×10⁻⁵ M

                                      TABLE III                                   __________________________________________________________________________    Hydrogenation of the substrate N-benzylbenzoylformamide                       PhCOCONHCH.sub.2 Ph                                                                         Hydrogenation                                                                 rate (cm.sup.3 of                                                             hydrogen con-                                                                         Half-                                                   Ligand        sumed per                                                                             reaction                                                                            Enantriomeric                                     L       L:Rh ratio                                                                          minute) time (min)                                                                          excess (%)                                                                            Configuration                             __________________________________________________________________________    CyProNOP                                                                              1.1   2.3     43    86.6    S                                         CyProNHOP                                                                             1.1   0.6     200   48.7    S                                         CyProNHOP                                                                             2.2   0.65    200   49.7    S                                         CyThreoNOP                                                                            1.1   1.8     67    81.5    S                                         CyAlaNOP                                                                              1.1   2       55    74.4    S                                         i-PrProNOP                                                                            1.1   1.5     70    77      S                                         ProNOP.sup.(a)                                                                        1.1   --      --    46      S                                         Pro-BuNOP.sup.(a)                                                                     1.1   --      --    49.3    S                                         __________________________________________________________________________

Experimental Conditions

[Rh]=2×10⁻³ M; [S]:[Rh]=200

Solvent: benzene (30 cm³)

Temperature: 25° C.

Pressure: approximately 1 bar

Yield: greater than 90%

(a): Different reaction conditions, which are: pressure 40 bars;temperature 30° C. and reaction time 12 h.

                  TABLE IV                                                        ______________________________________                                        Effect of the molar ratio [S]:[Rh] during the reduction of                    N-benzylbenzoylformamide PhCOCONHCH.sub.2 with the system                     "Rh.CyProNOP. Cl"                                                                             Half-                                                         Substrate       reaction  Yield Enantiomeric                                                                           Config-                              (S)    Solvent  time (min)                                                                              (%)   excess (%)                                                                             uration                              ______________________________________                                        200    Benzene  55        95    85.6     (S)                                  400    Benzene  60        90    85.5     (S)                                  1000   Benzene  62        98    83       (S)                                  5000   Benzene  60        91    86       (S)                                  200    Ethanol  170       88    72       (S)                                  400    Ethanol  185       92    43.7     (S)                                  ______________________________________                                    

Experimental Conditions

[S]=0.4M

[L]:[Rh]=1.1

Solvent: benzene (30 cm³)

Temperature: 25° C.

Pressure: approximately 1 bar

We claim:
 1. A process for the asymmetric hydrogenation of the carbonylmoiety of a carbonyl compound comprising the step of contacting acarbonyl moiety of a carbonyl compound with hydrogen in the presence ofat least one transition metal complex of the formula:

    MZq

in which M is a group VIII metal of the Periodic Table; Z is at leastone ligand selected from the group consisting of atoms and moleculescapable of complexing the metal M; and q is the coordination number ofthe metal M,and at least one chiral phosphorus-containing ligand of theformula (I): ##STR11## in which: R is a hydrocarbon radical selectedfrom the group consisting of straight-chain or branched alkyl,cyclo-alkyl and aryl radicals; R¹ is a hydrogen, a hydrocarbon radicalor a --PR₂ residue; R² is a hydrogen or a hydrocarbon radical; R³ andR⁴, which are necessarily different, are selected from the groupconsisting of hydrogen atoms, hydrocarbon radicals and hydrocarbonradicals carrying at least one group selected from the group consistingof alcohol, thiol, thioether, amine, imine, acid, ester, amide and ethergroups; and R⁵ and R⁶ are selected from the group consisting of hydrogenatoms, hydrocarbon radicals and functionalized hydrocarbon radicals; itbeing possible for one of the radicals R³ and R⁴ to carry an --OPR₂ or--NPR₂ group, both R⁵ and R⁶ being, in this case, equal to hydrogen whenR¹ represents --PR₂, it being possible for R² and R³ and the nitrogenand carbon atoms which carry them respectively to together form a 5- or6-membered heterocycle, or alternatively, it being possible for R² andR⁵, the nitrogen and carbon atoms which carry them respectively and theintermediate carbon atoms to together form a 5- or 6-memberedheterocycle, to thereby asymmetrically hydrogenate said carbonyl moietyof said carbonyl compound.
 2. The process as claimed in claim 1, whereinfor R the straight chain or branched alkyl radical is a C₁ -C₁₂ alkylradical.
 3. The process as claimed in claim 1, wherein for R thecycloalkyl radical is a cyclohexyl or cyclopentyl radical.
 4. Theprocess as claimed in claim 1, wherein for R the aryl radical is aphenyl radical.
 5. The process as claimed in claim 1, wherein for R¹ andR² the hydrocarbon radical is a C₁ -Cl₂ alkyl radical.
 6. The process asclaimed in claim 1, wherein for R³ and R⁴ the hydrocarbon radical is amethyl, isopropyl, isobutyl, isoamyl, neobutyl, hydroxymethyl,n-hydroxyethyl, iso-hydroxyethyl, n-aminobutyl, 4-methyleneimidazolyl,N-n-propylguanidyl, ethanoyl, acetamido, n-propionyl, n-propionamido,phenyl, benzyl, para-hydroxybenzyl, 3-methyleneindolyl, methanethioyl,mercaptomethyl or NH₂ --C(═NH)--NH(CH₂)₃ -- group.
 7. The process asclaimed in claim 1, wherein for R⁵ and R⁶ the hydrocarbon radical is aC₁ -C₁₂ alkyl radical.
 8. The process as claimed in claim 1, wherein themetal M of the complex MZq is iron, nickel, cobalt, rhodium, ruthenium,iridium, palladium or platinum.
 9. The process as claimed in claim 1,wherein the atom or molecule Z of the complex MZq is carbon monoxide,halogens, ethylene, norbornadiene, cyclooctadiene or acetylacetone. 10.The process as claimed in claim 1, wherein q of the complex MZq is avalue between 2 and 6 inclusive.
 11. The process as claimed in claim 1,wherein the hydrogenation is carried out in the presence of at least oneagent capable of taking up a ligand Z from the constituent MZq, it beingpossible for this agent to be either an acid having an anion A⁻ whichhas a low complexing capacity and which is sterically hindered or ametal salt of such an acid, or a quantity of electricity applied byelectrolysis at an applied cathode potential.
 12. The process as claimedin claim 1, wherein the hydrogenation is carried out in the presence ofat least one activator selected from aluminum-containing derivatives offormula AlR'_(n) X_(3-n), in which n has a value from 0 to 3, X is ahalogen atom and R' is an alkyl radical containing from 1 to 12 carbonatoms.
 13. The process as claimed in claim 1, wherein the reaction iscarried out using a molar ratio ligand of formula (I): complex MZq ofbetween 1 and
 10. 14. The process as claimed in claim 11, wherein thereaction is carried out using a molar ratio agent capable of capturing aligand Z:complex MZq less than or equal to q.
 15. The process as claimedin claim 12, wherein the reaction is carried out using a molar ratioactivator:complex MZq of between 0.1 and
 10. 16. The process as claimedin claim 1, wherein the reaction is carried out at a temperature ofbetween -20° C. and 200° C. and at a pressure of between 1 and 200 bars.17. The process as claimed in claim 1, wherein the reaction is carriedout in a medium in which the carbonyl compound starting material issubstantially soluble, but in which the reaction product is insoluble orsubstantially insoluble.
 18. The process as claimed in claim 1, whereinthe reaction is carried out in a solvent selected from the groupconsisting of aromatic hydrocarbon solvents, aliphatic alcohols,aliphatic and alicyclic ethers and their mixtures.
 19. The process asclaimed in claim 1, wherein hydrogenation is carried out with asubstrate selected from the group consisting of α-keto amides andα-dicarbonyl compounds.
 20. The process as claimed in claim 2, whereinthe straight chain or branched alkyl radical is methyl, ethyl,isopropyl, or tert-butyl.
 21. The process as claimed in claim 17,wherein the molar ratio of carbonyl compound starting material tocatalyst is at least 5,000 to
 1. 22. The process as claimed in claim 21,wherein the molar ratio of carbonyl compound starting material tocatalyst is at least 10,000 to
 1. 23. The process as claimed in claim19, wherein the α-keto amides are selected from the group consisting ofN-benzylbenzoyl-formamide and N-benzyl-4-hydroxybenzoylformamide and theα-dicarbonyl compounds are selected from the group consisting of2-oxo-3,3-dimethyl-1,4-butanolide and α-keto esters.